Key advances in obesity research over the last decade have established the prominence of the central nervous system (CNS) in body weight regulation. The goal of the proposed research is to develop a target discovery approach that will mine neurons in the CNS known to express important obesity genes. This goal will be accomplished using recently-developed state-of-the-art techniques to genetically tag and then isolate, from the intact brain, specific neuronal subtypes already known to be important for body weight regulation. We will then catalog the transcriptome of these "obesity neurons" and determine gene expression profiles of these neurons under conditions designed to reveal gene function. The identification of genes selectively expressed in specific neuronal subtypes will provide the molecular raw material for the next generation of anti-obesity drug targets. The proposed approach for CNS target discovery combines three core technologies: (1) genetic tagging of neuronal subpopulations with modified bacterial artificial chromosome (BAC) transgenes, (2) harvesting of tagged "obesity neurons" and (3) RNA expression profiling analysis of the captured "obesity neurons" under conditions designed to reveal gene function. The ultimate commercial aim is to sell or license validated CNS anti-obesity drug targets, target-specific high through-put assays, and chemical leads for these targets. PROPOSED COMMERCIAL APPLICATION: The optimized drug discovery platform derived from this research will serve as a standardized method for identifying various CNS drug targets, not only those involved in obesity. The commercial value of the platform will be realized through the quality of targets and by the potential chemical leads developed against these targets.